Nucleic acids interact with a variety of compounds including metal complexes, antibiotics, carcinogens and biological stains. Extensive studies in the past decades have shown that these interactions are basically due to intercalation, groove binding and covalent bonding which are often reinforced by hydrogen bonding and/or coulombic interaction. The main objective of this research is to characterize each of these modes of interactions by resonance Raman (RR) and aqueous IR spectroscopy. The ultimate goal of our research is to establish spectra-structure- biological activity relationships which will serve as a guide in designing clinically useful drugs. We will initiate our research by studying the interaction of nucleic acids with a series of water-soluble metalloporphyrins (M(TMpy-P4)) since there is abundant structural and spectroscopic information concerning these porphyrins as well as an indication that their iron derivatives possess antitumor properties. These porphyrins are known to be intercalated between base-pairs (Cu, Ni) or bound to the groove (Zn, Co) of DNA. We propose two experiments to distinguish these two types: (1) Measurements of frequency shifts and hypo/hyper-chromicity of their RR bands resulting from interaction with DNA. The latter includes excitation profile studies. (2) Orientation dependence of their RR bands in a gradient of flow velocity. If clear-cut criteria for distinguishing intercalation and groove-binding are established, we will apply them to the interaction of naturally occurring porphyrins (proto/hemato-porphyrin derivatives) since hematoporphyrin derivatives are clinically important. We will also measure the RR spectra of these porphyrins complexed to DNA by using pulse laser excitation. This should provide valuable information about the structure, force field and lifetime of such a complex in the electronic excited state. We will examine vibrational characteristics of drugs which are complexed to nucleic acids via covalent bonding, hydrogen bonding and coulombic interaction. The base-pair sequence specificity of a drug will be examined by UV-RR spectroscopy. In these experiments, a specific drug will be reacted with a series of oligonucleotides of known base-pair sequences and the UV-RR spectra of the latter will be compared. Finally, we will measure RR spectra of Bleomycin model compounds complexed to DNA to obtain structural information about reaction intermediates involved in DNA strand scission.